tbuckley/cabot-search huggingface dataset:
Abstract 477: Discovery of RGT-018: A potent, selective and orally bioavailable SOS1 inhibitor for mutant KRAS-driven cancers
Authors: Fei Xiao, Kailiang Wang, Xinjuan Wang, Huijuan Li, Zhilong Hu, Wei Huang, Xiaoming Ren, Teng Feng, Lili Yao, Jing Lin, Chunlai Li, Liufeng Mei, Zhuanzhuan Zhang, Yangyang Liu, Xi Chen, Xiaotian Zhu, Wenge Zhong, Zhi Xie
Journal: Cancer Research (2023)

Abstract Background: KRAS is the most frequently mutated oncogene with high prevalence in non-small cell lung cancers (NSCLC), colorectal cancers (CRC), and pancreatic cancers (PAC). FDA currently approved sotorasib provides breakthrough therapy for cancer patients with KRASG12C mutation, however there is still high unmet medical need for new agents that target a broader KRAS mutated tumors. A new opportunity emerges to develop a pan KRAS inhibitor by suppressing the upstream guanine nucleotide exchange factor (GEF) protein son of sevenless 1 (SOS1). SOS1 is a key activator of KRAS and facilitates the conversion of GDP-bound KRAS (off) state to GTP-bound KRAS (on) state. Binding to its catalytic domain, small molecule SOS1 inhibitor prevents KRAS activation and suppresses cancer cell proliferation. Material and Methods: Regor’s unique Computer Accelerated Rational Design (CARD) technology platform was applied to identify potent and selective SOS1 inhibitors. Biochemical assays and cellular assays were utilized to drive the structure-activity relationship (SAR). In vitro and in vivo target engagement were confirmed. In vivo efficacy study data were generated using lung and pancreatic cancer xenograft mouse models with KRAS mutation. Results: In vitro, RGT-018 blocked the interaction of KRAS::SOS1 with high selectivity, and inhibited proliferation of a broad spectrum of mutant KRAS-driven cancer cells as a single agent. Robust anti-proliferation activity was observed when RGT-018 was combined with MEK, KRASG12C, EGFR or CDK2/4/6 inhibitors in vitro. Oral administration of RGT-018 inhibited tumor growth and suppressed KRAS signaling pathway activation in tumor xenografts. Furthermore, combination with MEK or KRASG12C inhibitors led to profound tumor regression. Conclusions: The pharmacological properties of RGT-018 represent an attractive drug candidate with oral bioavailability for combination with targeted agents to treat a broader patient population driven by mutant KRAS. Citation Format: Fei Xiao, Kailiang Wang, Xinjuan Wang, Huijuan Li, Zhilong Hu, Wei Huang, Xiaoming Ren, Teng Feng, Lili Yao, Jing Lin, Chunlai Li, Liufeng Mei, Zhuanzhuan Zhang, Yangyang Liu, Xi Chen, Xiaotian Zhu, Wenge Zhong, Zhi Xie. Discovery of RGT-018: A potent, selective and orally bioavailable SOS1 inhibitor for mutant KRAS-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 477.
Abstract 3967: CRISPR/Cas9 screening identified novel membrane targets sensitizing hepatocellular carcinoma cells to natural killer cell-mediated cytotoxicity
Authors: Shuo Li, Lin Han, Siyao Zhang, Guangfeng Geng, Lei Huo, Dawei Huang, Zhaoren He, Shuoran Li, Zhaoshi Jiang, James X. Rong
Journal: Cancer Research (2023)

Abstract Natural killer cells (NK) play a central role in cancer immune surveillance by directly killing cancer cells and producing pro-inflammatory cytokines to stimulate and recruit other immune cells to elaborate long-lasting anti-tumor responses. However, little is known about the immune escape mechanisms and regulatory proteins, particularly those for NK, involved in hepatocellular carcinoma (HCC), one of the most common and lethal cancers. To identify the determinants of NK killing function, we performed an HCC cell line-based CRISPR/Cas9 loss-of-function genetic screen, using a human whole membrane protein library containing ~7000 genes curated from 3 public membrane protein datasets. The human SNU449 was chosen as a representative HCC cell line for CRISPR/Cas9 editing based on the genetic profile analysis, representing one HCC patient subpopulation (&amp;gt; 30%) in the TCGA cohort. The cell line was incubated with NK92 cells at ratios of 2:1, 1:1, and 0.5:1. Bioinformatics methods for prioritizing genes (e.g., MAGeCK) were applied on 3 tested groups with different ratios. Single guide RNAs targeting genes in the antigen presentation machinery were depleted, including HLA-C, B2M, and TAP1/2, whereas components of the tumor-immune synapse, such as NCR3LG1 and ICAM1, were enriched, confirming the validity of the screen. SLC33A1 (an endosomal acetylCoA transporter) and SLC31A1 (the major copper influx transporter) were also depleted, previously unknown as NK regulators. The effects of SLC33A1 and SLC31A1 were validated in individual gene knockout cells generated respectively by lentiviral sgRNA expression. Furthermore, knockout of either transporter in SNU449 cells increased IFNγ secretion, confirming NK92 activation. Our results revealed that CRISPR/Cas9-based functional genomics screens in HCC cell lines could identify novel targets modulating NK-mediated killing. Further analysis of mechanisms of action, and particularly functional validation in in vivo systems, will potentially provide novel targets for the treatment of HCC. Citation Format: Shuo Li, Lin Han, Siyao Zhang, Guangfeng Geng, Lei Huo, Dawei Huang, Zhaoren He, Shuoran Li, Zhaoshi Jiang, James X. Rong. CRISPR/Cas9 screening identified novel membrane targets sensitizing hepatocellular carcinoma cells to natural killer cell-mediated cytotoxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3967.
Abstract 5344: Novel melanoma leads demonstrate efficacy in A375 xenograft model in nude mice
Authors: Dmitriy Minond, Sadeeshkumar Velayutham
Journal: Cancer Research (2023)

Abstract The purpose of this study was to evaluate efficacy of novel anti-melanoma leads for in vivo efficacy. Despite the recent advances in melanoma therapy, the need for new targets and novel approaches to therapy is urgent. We previously reported novel melanoma leads, 2155-14 and 2155-18, that work via binding and downregulating spliceosomal proteins hnRNPH1 and H2. To determine the therapeutic potential of these compounds we tested them in A375 cell-line derived xenograft in nu/nu mice. For determination of 2155-14 and 2155-18 potency in vivo, nude mice were inoculated subcutaneously with A375 cell line and tumors were allowed to reach 100mm3. Animals were then randomized into four groups to receive subcutaneous administration of vehicle, 10mg/kg vemurafenib, and 25mg/kg 2155-14 and 2155-18 three times per week for 15 days. The result revealed that both 2155-14 and 2155-18 significantly decreased the growth of A375 tumors, which was comparable to vemurafenib. These results are well correlated with the exposure of leads in plasma. In summary, these results suggest a therapeutic potential of targeting spliceosomal proteins hnRNPH1 and H2 and support potential of 2155-14 and 2155-18 as drug candidates for treatment of melanoma. Keywords: Melanoma, drug discovery, A375, xenograft. Citation Format: Dmitriy Minond, Sadeeshkumar Velayutham. Novel melanoma leads demonstrate efficacy in A375 xenograft model in nude mice. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5344.
Abstract 4262: Genomic profiling of uveal melanoma patients using the GENIE database
Authors: Shaden Tashtoush, Ashaar Al-Akhras, Alina Ghazou, Sebawe Syaj
Journal: Cancer Research (2023)

Abstract Uveal melanoma (UM) is the most common primary adult intraocular tumor. Frequently mutated genes in UM include BAP1, EIF1AX, GNA11, GNAQ CHEK2, and SF3B1. This study aims to investigate the genomic characteristics of UM patients using a large cohort of clinicogenomic data. We assessed the frequency of genetic mutations in UM patients obtained from the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) cohort v12.1. We excluded patients with samples from a local recurrence, not otherwise specified tumor samples, and data not collected for sampling localization from our cohort. A total of 296 UM patients were included in this study, 164 (55.4%) of which were male and 131 (44.6%) were female. The sample mean age was 59.5 (SD: 14.1), and most patients were of white ethnicity (83.8%). Of 243 patients with known vital status, 32.1% (n = 78) of them were alive, while 67.9% (n = 165) of them were deceased. Sequencing samples were collected from the primary tumor in 141 patients, and from a metastatic nodule in 146 patients. We found that GNAQ and GNA11 were mutated in 43.9% and 43.6% of patients, respectively. BAP1 was mutated in 35.1%, SF3B1 in 22.3%, and EIF1AX in 13.2% of patients. No patients had GNAQ and GNA11 mutations concurrently. All patients had a median mutation count of 3, with no differences between the two genders. No significant differences were found in the frequency of mutations in regard to gender. GNAQ and GNA11 mutations were identified to be the most frequent mutations among UM patients, with a mutual exclusivity relationship between the two genes. New therapeutic modalities should consider the comprehensive genomic profiling of UM patients to improve their overall survival rate and quality of life. Citation Format: Shaden Tashtoush, Ashaar Al-Akhras, Alina Ghazou, Sebawe Syaj. Genomic profiling of uveal melanoma patients using the GENIE database. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4262.
Abstract 4758: <i>SETD4</i> transcription levels correlates with leukemic burden and <i>SMYD2</i> transcription in acute lymphoblastic leukemia
Authors: Luis Augusto Muniz Telles, Luis Henrique Sakamoto, Alan Jhones Assis, Doralina de Amaral Rabello, Andrea Barretto Motoyama, Fabio Pittella-Silva
Journal: Cancer Research (2023)

Abstract Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy worldwide. It has a history of great rates of success in treatment, but adults and infants still share a dismal prognosis. This condition makes the development of new prognostic markers linked to effective therapeutic strategies a matter of pressing concern. While cancer has traditionally been viewed as a genetic disease derived from alterations in oncogenes and tumor suppressors, it is well known nowadays that epigenetic changes also play a fundamental role in tumorigenesis. The SET family of lysine methyltransferases (KMT) has been implicated in a number of cancers, and SETD4 is a member that is still poorly characterized. In the present study we used qPCR to analyze the expression pattern of SETD4 among 83 pediatric ALL patients and non-neoplastic bone marrow (BM) samples and investigated the correlation between SETD4 transcription changes with the leukemic burden in ALL patients during chemotherapy. We found that SETD4 transcription levels are significantly upregulated in BM samples derived from ALL patients compared to non-neoplastic BM (8,5-fold higher, p &amp;lt; 0,001) and its expression correlated with leukemic burden. Importantly, levels of SETD4 decreased in patients that responded to chemotherapy treatment. We further investigated whether SETD4 transcription levels associates with that of SMYD2, another KMT previously identified as a prognostic marker in ALL. Transcription levels of SETD4 and SMYD2 were examined on day 15th and 29th of chemotherapy. Surprisingly, a high level of correlation (Spearman r = 0.925, p &amp;lt; 0.01) between both genes was observed in both treatment time points. Finally, survival outcomes were worst in ALL patients with high levels of SETD4 transcription (log-rank test, p &amp;lt; 0,05), evidencing its dysregulated expression is associated with an unfavorable disease prognosis. Together, these results point to SETD4 as a useful prognostic marker, a possible tool to assess response to therapy and an attractive target for drug development. Citation Format: Luis Augusto Muniz Telles, Luis Henrique Sakamoto, Alan Jhones Assis, Doralina de Amaral Rabello, Andrea Barretto Motoyama, Fabio Pittella-Silva. SETD4 transcription levels correlates with leukemic burden and SMYD2 transcription in acute lymphoblastic leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4758.
Abstract 3367: Tumor-derived Extracellular Vesicles as a potential PD biomarker for TEAD central pocket binder activity in liquid biopsy
Authors: Manoel Nunes, Emmanuel Spanakis, Wilson Dos-Santos-Bele, Emilia Rabia, Stephane Soubigou, Gaelle Muzard, Odette Dos-Santos, Jack Pollard, Angela Hadjipanayis, Fabien Delahaye, Olivier Venier, Laurent Debussche, Don Jackson, Colette Dib, Iris Valtingojer, Matteo Cesaroni
Journal: Cancer Research (2023)

Abstract We assessed the utility of mRNAs in extracellular vesicles as biomarkers for inhibition of YAP1/TEAD signaling by the TEAD central pocket inhibitor. The field of liquid biopsies is of enormous interest for noninvasive monitoring of cancer progression and response to treatment. Extracellular Vesicles (EVs) such as exosomes, microvesicles, and apoptotic bodies, are nanoparticles found in all biological fluids. These cell-derived, small secreted vesicles convey biological information, either by surface-to-surface interaction or by shuttling bioactive molecules to a recipient cell’s cytoplasm. Because EVs harbor the cargos of their original cells, their contents may be useful as biomarkers to follow drug activity. (F. Urabi et al., 2020). We compared the effects of YAP1/TEAD inhibitor treatment on intracellular and EV-encapsulated mRNAs in three compound-sensitive tumor cell lines (and one insensitive cell line) based on TEAD inhibitor IC50 assay profiles. Cell lines were treated at four doses of YAP1/TEAD inhibitor (0.0 µM, 0.3 µM, 1.0 µM &amp; 3.0 µM) for 24h. EVs and intracellular RNAs were isolated and profiled by RNAseq. To estimate YAP1/TEAD pathway activity, we used a transcriptomic signature identified previously by our group (L. Calvet et al., 2022) and we showed that the effects of YAP1/TEAD inhibitor treatment on the YAP1/TEAD score in intracellular mRNAs corresponded to a decrease of the score in EV-secreted RNAs. In addition, we ran an unbiased analysis to identify single transcripts in the EVs that were modulated by YAP1/TEAD inhibitor. One of the best markers identified by regression analysis was CYR61, that is part of the signature and is a well-established downstream target of YAP/TEAD pathway. In conclusion, these results suggest that the YAP1/TEAD signature in EV mRNAs represents a relevant PD biomarker to monitor YAP1/TEAD inhibitor activity and could potentially serve as a noninvasive liquid biopsy-based biomarker detection in the clinic. Citation Format: Manoel Nunes, Emmanuel Spanakis, Wilson Dos-Santos-Bele, Emilia Rabia, Stephane Soubigou, Gaelle Muzard, Odette Dos-Santos, Jack Pollard, Angela Hadjipanayis, Fabien Delahaye, Olivier Venier, Laurent Debussche, Don Jackson, Colette Dib, Iris Valtingojer, Matteo Cesaroni. Tumor-derived Extracellular Vesicles as a potential PD biomarker for TEAD central pocket binder activity in liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3367.
Abstract 1493: ROS inhibits enzymatic activation of PRMT5 and increases the protein stability of tumor suppressors as non-histone substrates in liver cancer
Authors: Ji Min Lee, Hyunkyung Kim, Hyuntae Im, Hee-ji Baek
Journal: Cancer Research (2023)

Abstract Retinoic acid receptor-related orphan receptor α (RORα) and p53 are transcription factors involved in nuclear gene expression and known tumor suppressors. RORα was the first identified substrate of lysine methylation-dependent degradation. However, the mechanisms of other post-translational modifications (PTMs) that occur in RORα and p53 remain largely unknown, especially in liver cancer. Arginine methylation is a common PTM in arginine residues of nonhistone and histone proteins and affects substrate protein function and fate. We found an analogous amino acid disposition containing R37 at the ROR N-terminus compared to histone H3 residue, which is arginine methylated. Here, we provide evidence that R37 methylation-dependent degradation is carried out by protein arginine methyltransferase 5 (PRMT5). In addition, we discovered that PRMT5 regulated the interaction between the E3 ubiquitin ligase ITCH and RORα through RORα arginine methylation. Arginine methylation-dependent ubiquitination-mediated RORα degradation reduced downstream target gene activation. H2O2-induced reactive oxygen species (ROS) decreased PRMT5 protein levels, consequently increasing RORα protein levels in liver cancer in vitro and in vivo. Furthermore, the enzymatic activities of PRMT5 were directly affected by ROS via the dissociation of PRMT5-Mep50 octamer in the methylosome complex. Taken together, ROS inhibited liver cancer progression by inducing apoptosis via PRMT5-mediated methylation of RORα combined with other histone and non-histone substrates and the ITCH axis. Our results potentiate PRMT5 as an elimination target in cancer therapy, and this additional regulatory level within ROS signaling may help identify new targets for therapeutic intervention in liver cancer. Citation Format: Ji Min Lee, Hyunkyung Kim, Hyuntae Im, Hee-ji Baek. ROS inhibits enzymatic activation of PRMT5 and increases the protein stability of tumor suppressors as non-histone substrates in liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1493.
Abstract 5442: SlideQC: An AI-based tool for automated quality control of whole-slide digital pathology images
Authors: Daniela Rodrigues, Stefan Reinhard, Therese Waldburger, Daniel Martin, Suzana Couto, Inti Zlobec, Peter Caie, Erik Burlingame
Journal: Cancer Research (2023)

Abstract Introduction: Artifacts are often introduced during tissue collection and processing, slide preparation, and/or when generating whole slide images (WSI). The presence of artifacts has a negative impact on the digital pathology workflow as artifacts may hinder diagnostic reporting and can lead to false positive and false negative results when using image analysis algorithms or computer-aided diagnosis systems. Manual quality control of WSI is a time-consuming procedure and therefore automated quality control tools, which report and exclude artifacts, are highly desirable to streamline digital pathology workflows. To automate the quality control step, we developed SlideQC, an AI-based quality control tool that automatically detects, reports, and outlines artifacts such as air bubbles, dust/debris, folds, out-of-focus,and pen marks, in both research and clinical workflows. Methods: SlideQC was trained with a DenseNet-based network using 1984 annotations for artifacts including air bubbles, dust/debris, folds, out-of-focus, and pen markers, across 254 Haematoxylin and Eosin (H&amp;E) stained WSI from more than 9 tissue types. A set of 2048 annotations from synthetically generated out-of-focus images was added to supplement the training data. The performance of the SlideQC was evaluated on an external test cohort of 49 WSI H&amp;E images sourced from the open-source database ‘HistoQCRepo’, across 375 annotations (tissue and artifact), and compared with the performance of HistoQC, an open-source quality control tool for digital pathology slides. Results: On the external test cohort, SlideQC showed high sensitivity, specificity, and F1-score with average values of 0.93, 0.99, and 0.93, across the five artifact types. In the same cohort, HistoQC attained an average sensitivity, specificity, and F1-score of 0.65, 0.79, and 0.54, respectively. Conclusions: SlideQC achieved high sensitivity, specificity, and F1-score on an external test cohort. SlideQC can add efficiency gains to a workflow by performing quality control on 100% of slides rather than the currently manually performed on only a subset of the slides in clinical pathology departments. SlideQC can allowthe triaging and alerting of slides containing a high level of artifact within a digital pathology workflow. The tool can also be used to exclude the artifact region from downstream analysis by subsequent image analysis algorithms. Citation Format: Daniela Rodrigues, Stefan Reinhard, Therese Waldburger, Daniel Martin, Suzana Couto, Inti Zlobec, Peter Caie, Erik Burlingame. SlideQC: An AI-based tool for automated quality control of whole-slide digital pathology images. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5442.